Chemokine Receptors

According to recent researches, γδ T cells are seemingly an ideal model to study the role of chemokine receptors in tissue-specific lymphocyte homing. However, like their ligands and functions, their homing pathways remain largely unknown. It will be of great interest to determine how subset-specific chemokine receptor expression helps target these populations to distinct sites, and aids in the functional biology of these enigmatic cells.

Introduction to Chemokines

Chemokines are chemotactic cytokines that control cell migration and cell positioning throughout development, homeostasis, and inflammation. Chemokines encompass a group of small (8-12 kDa) heparin-binding cytokines with the ability to induce leukocyte migration. Virtually, any cell type can express and secrete chemokines upon stimulation, including endothelial, epithelial, and stromal cells as well as leukocytes. Chemokines can operate as a soluble gradient to induce chemotaxis or after being immobilized on, for instance, the endothelial glycocalyx via glycosaminoglycan binding or within the extracellular matrix. This process allows multiple chemokines to be sequestered, often in multimeric forms, at sites of inflammation and prevents them from being washed away, facilitates chemokine localization by leukocytes, and increases their affinity toward cognate receptors. Immobilized chemokines can also persist at higher local concentrations than the freely diffusible state while enhancing the function of one another in a phenomenon referred to as chemokine cooperativity.

Fig.1 The role of chemokines and their receptors in homeostasis and disease. (Tang, 2018)

Chemokines and γδ T Cells

• Interaction between chemokines and γδ T Cells

More recently, it was shown by RNase protection assay that phosphoantigen-activated Vδ2 γδ T cell lines rapidly down-regulated their expression of CC chemokine receptors, most notably CCR5, following re-exposure to the synthetic phosphoantigen isopentenyl pyrophosphate (IPP). In addition, CXCR3 expression was found on TCR γδ-expressing thymocytes that migrated in response to the corresponding ligands IP-10 (CXCL10), monokine-induced by IFN-γ (or CXCL9), and IFN-inducible T cell α-chemo-attractant (or CXCL11).

• γδ T cells migrate in response to chemokines

The migration of γδ T lymphocytes into tissues is straightly controlled by chemo-attractant factors, such as chemokines. Therefore, in parallel with the pattern of chemokine production, the expression of chemokine receptors is determinant for lymphocyte trafficking during physiological and inflammatory conditions. Several members of the CC and CXC chemokine families and their counterpart receptors have been shown to account for γδ T lymphocyte recruitment in different responses induced by pathogenic antigens. Functional studies with purified γδ T cells and γδ T cell clones indicate that human γδ T cells migrate in response to CC chemokines such as monocyte chemo-attractant protein 1 (MCP-1 or CCL2), RANTES (CCL5), macrophage inflammatory protein 1α (MIP-1α or CCL3), and MIP-1β (CCL4), but not in response to CXC chemokines IL-8 (CXCL8) or IFN-inducible protein 10 (IP-10 or CXCL10).

• Chemokines secretion in activated γδ T cells

Activated γδ T cells exhibit broad cytotoxic activities against a wide variety of tumor cells, in which they utilize death receptor/ligand (e.g., Fas/Fas-ligand)-dependent and perforin/granzyme- or granulysin-dependent pathways. γδ T cells secrete various cytokines and chemokines including proinflammatory Th1-like cytokines such as IFN-γ and TNF-α, and contribute to the reduced survival of autologous tumor cells. Besides, they also produce Th2 cytokines such as IL-4 in the bronchoalveolar lavage fluid of patients with allergic asthma.

Fig.2 Activated γδ T cells secrete a variety of cytokines and chemokines. (Wu, 2014)

• Chemokine receptor expression by γδ T cells

Bloodborne γδ T cells represent a potentially diverse population of cells homing to a myriad of sites. Consistent with this diversity, γδ T from peripheral blood express a wide variety of chemokine receptors including CCR1, CCR2, CCR5, CCR6, CCR7, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and CXCR6. From the diverse complement of chemokine receptors expressed, it is clear that understanding the role of chemokines in γδ T cell homing must include a subset-by-subset analysis. Gene knockout studies have suggested a role for CCR9 in γδ T cell homing to the intestinal epithelium.

At this point, studying the relationship between chemokine and γδ T cells is necessary. Devoted to γδ T cells research for years, Creative Biolabs provides comprehensive chemokine receptors services including γδ T chemokine receptors repertoires analysis, γδ T chemokine receptors transcriptome analysis, γδ T chemokine receptors generation, and γδ T chemokine receptors ligand reaction analysis.

If you need more information, please feel free to contact us.

References

1. Tang, P.; Wang, J. M. Chemokines: The past, the present and the future. Cell Mol Immunol. 2018, 15(4): 295-298.
2. Wu, Y.-L.; et al. γδ T cells and their potential for immunotherapy. International Journal of Biological Sciences. 2014, 10(2): 119-135.